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Iodine Allergy and Contrast Administration

Patients are frequently asked about iodine or seafood allergy before IV contrast material is administered because of a commonly held belief among radiologists and others in the medical community of a specific cross-reactivity between iodinated radiographic contrast material and other iodine-rich substances. "Iodine allergy" is often used as a collective term for adverse reactions to these agents. Patients commonly provide positive or ambiguous responses to such questions; such responses are likely to become more common with the increasing consumption of seafood and the increasing prevalence of allergies in the general population. Our purpose is to show that iodine does not confer a specific cross-reactivity between iodine-rich substances, that the cross-reactivity that does exist is nonspecific, and that the concept of iodine allergy is fallacious and may result in the inappropriate nonuse of IV contrast material in patients intolerant of antiseptics or seafood that contain iodine.

Background Physiology and Immunology

Iodine is an essential trace mineral, required for the synthesis of thyroid hormones. Ingested iodine is converted to iodide, the ionized form of iodine, in the gut. Dietary sources include fish, iodized salt, and iodates used as bread preservatives. Fish is a good source of iodine because, over the millennia, iodine has been leached from the soil and washed into the oceans. Iodine in fish may be free, as a substituent for chlorine, or bound to protein.

To briefly review, the immune system consists of nonspecific and specific responses. Mediators of nonspecific responses include phagocytes, complement, and interferon. Specific immune responses, which require an antigen-antibody interaction, are mediated by B and T lymphocytes. Simple atoms or molecules such as iodine or contrast material do not have the complexity required for antigenicity, although theoretically they might act as haptens. Haptens are agents that are too small to act as antigens by themselves but that, by binding to larger carrier molecules, provoke an antibody response to the hapten-carrier complex. Allergy, or hypersensitivity, is a specific, excessive immune response to an antigen and results in damage to the host. The most common type is immunoglobulin E-mediated and is known as anaphylactic or immediate hypersensitivity.

Iodine and Contrast Material Reactions

Contrast materials are triiodinated benzoic acid derivatives that, in solution, contain a small amount of free iodide. Adverse reactions to these substances may be classified as idiosyncratic or nonidiosyncratic.

The mechanism of idiosyncratic reactions is unknown. Among the theories for such reactions is the allergy theory, which proposes that either contrast material or iodine acts as a hapten, thus, provoking a specific immune response. An antigen-antibody reaction then occurs when the patient is subsequently re-exposed to contrast material. Contrast materials can cause the formation of antigenic iodoproteins in vitro [1]. However, the same group of investigators subsequently failed to show a significant relationship between contrast sensitivity and the presence of lymphocytes specifically reactive to either contrast material or iodide [2]. Additionally, attempts to induce antibody formation in vivo using an animal model have been unsuccessful, despite optimal conditions [3]. The mechanism of idiosyncratic contrast reactions is therefore unlikely to be a specific immune response (i.e., true allergy) and is more likely due to activation of complement or other mediators of the nonspecific immune system. Consequently, idiosyncratic contrast reactions are best termed "anaphylactoid," "allergy-like," or "pseudoallergic," rather than "allergic." Additionally, the activation is almost certainly a function of the contrast molecule as a whole rather than free iodide. For example, none of 23 patients with documented contrast sensitivity reacted to subcutaneous sodium iodide [4].

Nonidiosyncratic reactions are due to direct toxic or osmolar effects. The only adverse effect of contrast material that can convincingly be ascribed to free iodide is iodide mumps and other manifestations of iodism. "Iodide mumps" refers to swelling of the submandibular, sublingual, and parotid salivary glands after the administration of intravascular contrast material. It is part of a continuum of nonidiosyncratic reactions that are due to overload of normal physiologic pathways of iodide metabolism. This continuum is known as iodism; it also includes lacrimal gland swelling, coryza, and skin rashes. Most cases occur in patients with renal impairment, presumably because reduced renal excretion results in a higher in vivo iodide concentration.

Iodine and Seafood Intolerance

"Food intolerance" is a general term that includes all exaggerated or abnormal reactions to food, whether caused by immune or nonimmune mechanisms. For example, food-borne illness caused by fish and shellfish may be due to allergy, transmittal of infection, or the presence of toxins. These different mechanisms are of largely academic interest to the radiologist, because they may not be distinguishable in a patient with a history of illness after seafood ingestion. Nonetheless, accurate use of terminology suggests that such patients are best described as seafood-intolerant rather than seafood-allergic.

Hypersensitivity reactions to seafood almost always commence within 2 hr of exposure [4]. Symptoms include pruritus, urticaria, angioedema, bronchospasm, rhinitis, vomiting, diarrhea, and shock. The manifestations may be life threatening, even if initial symptoms are minimal (e.g., tingling in the mouth or throat). The reactions are true allergies and are probably immunoglobulin E-mediated. For example, 85% of patients with shellfish sensitivity have positive skin-prick tests to shrimp extract, the method of choice for revealing tissue immunoglobulin E. The responsible seafood antigen is at least partially characterized as the fish equivalent of the muscle protein tropomyosin [4]. No evidence exists that the iodine content of seafood is related to these reactions.

Iodine and Antiseptics

The active agent in many commercially available antiseptics is polyvinylpyrrolidone-iodine. Examples include Betadine (Purdue Frederick, Norwalk, CT) and Povidine (Alpharma, Baltimore, MD). Polyvinylpyrrolidone (povidone) is a polymer similar to dextran. It acts as a carrier that delivers complexed diatomic iodine directly to the bacterial cell surface. Diatomic iodine is bactericidal, apparently because of inactivation of essential bacterial enzymes. Adverse cutaneous reactions to the compound are rare; only two reactions were recorded in 5000 applications. It is likely that many such reactions are due to skin irritation rather than allergy, and in any case the iodine component is probably not involved. None of five patients with a history of contact dermatitis after povidone-iodine reacted to patch testing with potassium iodide solution, whereas all reacted to povidone-iodine [5]. Systemic side effects are extremely rare. Transcutaneous absorption of iodide in neonates and in bum patients can result in iodism. One case of a systemic anaphylactoid reaction due to vaginal use of povidone-iodine has been reported [6].

Cross-Reactivity and Iodine Allergy

Evidence exists of a nonspecific cross-reactivity between contrast material sensitivity and allergy to seafood, as well as other foods. In a large review, 5% of 112,003 cases of intravascular ionic contrast administration resulted in a reaction. The relative risk of a reaction in patients with seafood allergy (diagnostic criteria unspecified) was 3.0, compared with 2.9 for those with allergy to eggs, milk, or chocolate; 2.6 for those with allergy to fruit and strawberries; and 2.2 for those with asthma [7]. In other words, a seafood allergy increases the risk of a contrast reaction by about the same factor, as does any other allergy. Additionally, these figures suggest that at least 85% of patients with seafood allergy receiving IV contrast material will not have an adverse reaction. This risk-benefit profile should be considered before patients with seafood allergy are denied IV contrast material or recommended for corticosteroid premedication. We are unaware of any investigation of contrast reactivity in patients intolerant of povidone-iodine.

The likely mechanisms of idiosyncratic contrast reactions, seafood allergies, and povidone-iodine dermatitis are distinct; they are activation of nonspecific immune mediators by the contrast molecule, immunoglobulin E-mediated hypersensitivity to fish muscle protein, and irritant contact dermatitis, respectively. Little evidence exists that elemental iodine or iodide is responsible for idiosyncratic contrast reactions or povidone-iodine dermatitis, and no evidence exists that it is involved in seafood allergy. The notion that iodine confers a specific cross-reactivity between these agents is unfounded. The term "iodine allergy" is therefore unfortunate, because it perpetuates muddled thinking and unsubstantiated beliefs. It should be abandoned and replaced by more neutral descriptive terms such as "contrast material sensitivity," "seafood intolerance," and "povidone-iodine dermatitis."

Clinical Implications

Patients reporting iodine or seafood allergy should be questioned as to the exact nature and severity of the reaction. If possible, seafood allergy should be distinguished from other causes of seafood intolerance. The presence of a seafood allergy places the patient at a threefold risk of an adverse reaction to contrast material. As with any other allergy, the nature and severity of the reaction should be considered when choosing the type of contrast material and when determining the need for a premedication regimen. Seafood allergy should not of itself be regarded as an absolute contraindication to the administration of IV contrast material. There is no reason to believe that iodine allergy based on skin reactions to topical antiseptics is of any specific relevance to the administration of IV contrast material.